SK13262003A3 - Anthranilic acid amides, method for production thereof and their use - Google Patents

Abstract

The invention relates to anthranilic acid amides, to a method for the production thereof, to their use as a medicament, and to pharmaceutical preparations containing these anthranilic acid amides. The anthranilic acid amides consist of compounds of formula (I) in which R(1) to (R7) have the meanings as cited in the claims, act upon the Kv1.5 potassium channel, and inhibit a potassium stream described as an "ultra-rapidly activating delayed rectifier" in the human cardiac atrium. The compounds are therefore especially suited as novel antiarrhythmic active substances, particularly for treating and preventing atrial arrhythmias, e.g. atrial fibrillation AF or atrial flutter.

Description

Technical field

The invention relates to compounds of formula I

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the meanings given below, their method of preparation and their use, in particular as medicaments.

BACKGROUND OF THE INVENTION

The compounds of the formula I according to the invention are not yet known. They act on the so-called Kv1.5-potassium channel and inhibit the flow of potassium in the atrium of the human heart, called ultra-rapidly activating delayed rectifier. These compounds are therefore particularly suitable as novel antiarrhythmic agents, in particular for the therapy and prophylaxis of atrial arrhythmias, for example atrial fibrillation (atrial fibrillation, AF) or atrial flutter (atrial flutter).

Atrial fibrillation (AF) and atrial flutter are the most common persistent cardiac arrhythmias. The frequency of their occurrence increases with increasing age and often have fatal outcomes such as stroke. For example, 1 million Americans per year suffer from atrial fibrillation and lead to more than 80,000 strokes each year in the US. Existing class 1 and III antiarrhythmic drugs reduce the number of recurring cases of atrial fibrillation, but find limited use for their potential proarrhythmic side effects. There is therefore a great demand for the development of better drugs for the treatment of atrial arrhythmias (S. Nattel, Am.

Heart J. 130, 1995, 1094-1106; Newer developments in the management of atrial fibrillation).

Most supraventricular arrhythmias have been shown to be associated with so-called reentry-surge waves. These waves occur when the heart tissue has a slow conductivity and at the same time very short refractory periods. Increasing myocardial refractory time by prolonging action potential is a recognized mechanism for ending or preventing arrhythmias (TJ Colatsky et al., Drug. Dev. Res. 19, 1990, 129-140; Potassium channels as targets for antiarrhythmic drug action). The length of the action potential is determined by the extent of repolarized K ⁺ -flows directed from the cell through different K ⁺ -channels. The so-called delayed rectifier I _k , which consists of 3 different components: IK _r , IK _S and IK _ur .

Most known class III antiarrhythmics (eg dofetilide, E4031 and d-sotalol) mainly or exclusively block the rapidly activating potassium channel IK _r, which can be detected in the cells of the human ventricle and in the atrium. However, these compounds have been shown to exhibit an increased proarrhythmic risk at low or normal heart rates, with arrhythmias referred to as torsades de pointes being observed (DM Roden, Am. J. Cardiol. 72, 1993, 44B-49B; Current status of class III antiarrhythmic drug therapy). In addition to this partially fatal risk at a lower frequency, it has been found that the efficacy of IK _r- blockers decreases under conditions of tachycardia where efficacy is just needed (negative use-dependence).

While some of these disadvantages can be overcome by using blockers probably slow-activating component (IK _s), their effectiveness has not yet been proven, because the blockers IK _s -channel there are no known clinical studies.

The particularly fast activating and very slow inactivating component of the delayed rectifier IK _ur (= ultra-rapidly activating delay3 ed rectifier), which corresponds to the Kv1.5-channel, plays a particularly important role in the duration of repolarization in the human atrium.

Thus, inhibiting the outgoing IK _ur- potassium flux compared to inhibiting IK _r and IK _S is a particularly effective method for prolonging or preventing atrial arrhythmias, respectively. Mathematical models of action potential in humans suggest that the positive effect of IK _ur blockade should be particularly pronounced under the pathological conditions of chronic atrial fibrillation (M. Ccurtemanche, RJ Ramirez, S. Nattel, Carcliovascular Research 1999, 42, 477-489: Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model).

In contrast to IK _r and IK _S , which are also found in the ventricle of the human heart, IK _ur plays an important role in the human atrium, but not in the ventricle. Therefore, the inhibition of IK _determine -toku, in contrast to the blockade of IK _r or _IKs, the risk of a proarrhythmic action on the ventricle pre excluded (Z. Wang et al., Cic. Res. D, 1993, 1061 to 1076: Sustained Depolarisation Induced Outward Current in Human Atrial Myocytes; GR Li et al., Circ. Res. 'S, 1996, 689-696: Evidence for Two Components of Delaed Rectifier K ^{+ -} Current in Human Ventricular Myocytes; GJ Amos et al., J. Physiol. 491, 1996, 31-50: Differences between outward currents of human atrial and subepicardial ventricular myocytes.

Antiarrhythmics which act via selective blockade of the IK _ur -toku respectively Kvl.5-channel, are not yet commercially available. Although many blocking activities for the Kv1.5-channel have been described for many pharmaceutical active substances (e.g. tedisamil, bupivacaine or sertindole), Kv1.5-blockade is only a side effect here, among other major activities of these substances.

WO 98 04 521 and WO 99 37 607 claim aminoindanes and aminotetrahydronaphthalenes as potassium channel blockers that block the Kv1.5-channel. Likewise, in WO 00 12 077, structurally related aminochromans are claimed as Kv1.5-blockers.

Patent application WO 99 62 891 claims thiazolidinones which also block the potassium channel. The applications WO 98 18 475 and WO 98 18 476 claims the use of various pyridazinones and phosphine oxides as antiarrhythmics which should act via blockade of the IK _ur · The same compounds are not previously described as immunosuppressants (WO 96 25 936). All the compounds in the above-mentioned patent applications are structurally quite different from the compounds of the present invention. No clinical data are known for any of the compounds claimed in the above applications. Since experience has shown that only a small proportion of substances that are effective in preclinical research successfully overcome all clinical obstacles up to the drug stage, the need for new promising compounds still remains.

It has now surprisingly been found that the anthranilic acid amides of the formula I according to the invention are potent blockers of the human Kv1.5-channel. They can therefore be used as novel antiarrhythmics with a particularly advantageous safety profile. These compounds are particularly suitable for the treatment of supraventricular arrhythmias, for example atrial fibrillation or atrial flutter.

These compounds can be used to terminate existing fibrillation or atrial flutter to restore sinus rhythm (cardioversion). In addition, these compounds reduce the susceptibility to new fibrillation (sinus rhythm retention, prophylaxis).

The compounds of the invention are not yet known. Some structurally related compounds are described in the publications discussed hereinafter.

For example, compounds A and B are listed (FEBS Letters 421, (1981), 217-220) as serine protease inhibitors. Compounds C and D and similar derivatives are described (J. Med. Chem. 11 (1968), 777-787) as precursors for the synthesis of tetraisoquinino [2,1-d] [1,4] benzodiazepines.

EP-OS 0 686 625 describes anthranilic acid derivatives and their use as cGMP-phosphodiesterase inhibitors. Most of the 144 compounds exemplified therein differ from those of Formula I, inter alia, by exchanging a sulfonyl group for a carbonyl group. Only three examples also contain a sulfonylamino substituent, of which compound E (Example 135 in EP-OS 0 686 625) is structurally most similar to the compounds of the present patent application.

Ischemic heart disease, angina pectoris, hypertension, pulmonary hypertension, heart failure and asthma are mentioned as possible indications for the claimed compounds. This is in no way to be understood as the use of these or similar compounds as antiarrhythmic drugs.

(E)

Ο

br

The European patent application EP-OS 0 947 500 claims a large, partially heterogeneous amount of compounds to act as prostaglandin E2 antagonists or agonists. Most of the anthranilic acid derivatives disclosed therein differ from the compounds of the present patent application, among other things, by the presence of a free carboxyl function.

European patent application EP-OS 0 491 525 describes anthranilamides with various five-membered heterocycles in the side chain, such as compound F, and their use in the treatment of diabetes.

ABOUT

None of these publications mention the potassium channel blocking action, so the action of structurally related compounds of formula I could not be expected.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I

A is -C _n H _2n -;

n is 0, 1, 2, 3, 4 or 5;

is an oxygen atom;

D is a bond or an oxygen atom;

E is -C _m H 2 _n -;

m is 0, 1, 2, 3, 4 or 5;

R ⁸ is H, alkyl having 1, 2, 3 or 4 carbon atoms or C _p H ₂ p R ^14; p is 0, 1, 2, 3, 4 or 5;

R ¹⁴ is a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, an aryl group or a heteroaryl group, wherein the aryl and heteroaryl group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, atom bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ⁹ is hydrogen or alkyl having 1, 2, 3, 4, 5 or carbon atoms;

R ¹⁰ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by 1 , 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH 2, COMe, NH ₂ OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹¹ is cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidyl, wherein the phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , of NO _2, CN, COMe, _NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, metyl9 a sulfonyl group and a methylsulfonylamino group;

R ¹² is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ group, OCF ₃ group, NO ₂ group, CN group, COOMe group, CONH ₂ group, COMe group, NH ₂ group, OH group , alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹³ is C _p H ₂ p R ¹⁴ ';

p is 0, 1, 2, 3, 4 or 5;

R ¹⁴ 'is cycloalkyl having 3, 4, 5 or 6 carbon atoms, tetrahydrofuranyl, tetrahydropyranyl, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, C 1 alkyl, 2, 3 or 4 carbon atoms, alkoxy of 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹⁵ is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms;

R ² is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

R ³ is an alkyl group having 3, 4, 5, 6 or 7 carbon atoms a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, a phenyl group or a naphthyl group, the phenyl or naphthyl group being unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF _3, a group OCF _3, the group NO _2, CN, COOMe, ΟΟΝΗ _2, COMe, NH _2, a group OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , OCHF ₂ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

as well as their pharmaceutically acceptable salts.

Preferred are compounds of formula I wherein

R ¹ is a group

It is -C _n H _2n -;

n is 0, 1, 2, 3, 4 or 5;

O is an oxygen atom;

D is a bond or an oxygen atom;

E is -C _m H ₂ m ^- ;

m is 0, 1, 2, 3, 4 or 5;

R ⁸ is H, alkyl having 1, 2, 3 or 4 carbon atoms or C _p H _2p -R ^14; p is 0, 1, 2, 3, 4 or 5;

R ¹⁴ is a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, an aryl group or a heteroaryl group, wherein the aryl and heteroaryl group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, atom bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , CCMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ⁹ is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;

R ¹⁰ is hydrogen, alkyl having 1, 2, 2 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by 1 , 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, Cl ₃ group, OCF ₃ group, a group NO _2, CN, COOMe, CONH ?, COMe, NH ₂ OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino group, sulfamoyl group, methylsulfonyl group and methylsulfonylamino group 12;

R ¹¹ is a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, a phenyl group or a pyridyl group, wherein the phenyl group and the pyridyl group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COM, COM ₂ , NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2 , 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹² is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ group, OCF ₃ group, NO ₂ group, CN group, COOMe group, CONH ₂ group, COMe group, NH ₂ group, OH group , alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹³ is C _p H _2p -R ¹⁴ ';

p is 0, 1, 2, 3, 4 or 5;

R ¹⁴ 'is cycloalkyl having 3, 4, 5 or 6 carbon atoms, tetrahydropyranyl, tetrahydrofuranyl, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, C 1 alkyl, 2, 3 or 4 carbon atoms, an alkoxy group having 1,

2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group and a methylsulfonylamino group;

R ² is H or alkyl having 1, 2, 3 or 4 carbon atoms;

R ³ is an alkyl group having 3, 4 or 5 carbon atoms, a phenyl group wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, CF group ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, 1, 2 alkoxy, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , OCHF ₂ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

as well as their pharmaceutically acceptable salts.

Particularly preferred are compounds of formula I wherein

R ¹ is a group

R \ ^R, R \ x 'R

N A E n8

R \ r ^{12 R} SX 'RNAE or 9 10 10 ¹³ \ / ^R \ ΧΧ ^ Χ

N A E

A is -C _n H _2n -;

n is 0, -1, 2 or 3;

O is an oxygen atom;

D is a bond or an oxygen atom;

E is -C _m H _2in -;

m is 0, 1, 2 or 3;

R ⁸ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms;

R ⁹ is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;

R ¹⁰ is hydrogen, alkyl with 1, 2, 3 or 4 carbon carbon or cycloalkyl s 3, 4 or 5 carbon alkyl; R ¹¹ is a cycloalkyl group having 3,4, 5 or 6 carbon alkyl, phenyl or pyridyl group,

wherein the phenyl group and the pyridyl group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a CF ₃ group, an OCF ₃ group, a NO ₂ group, a CN group, a COMe group OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹² is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4 or 5 carbon atoms, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, CF ₃ group, OCF 3 group, NO 2 group, CN group, COOMe group, CONH 2 group, COMe group, OH group, alkyl group having 1, 2, 3 or 4 atoms carbon, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹³ is a group C _p H 2p -R ¹⁴ ';

p is 0, 1, 2, 3, 4 or 5;

R ¹⁴ 'is cycloalkyl having 3, 4, 5 or 6 carbon atoms, tetrahydrofuranyl, tetrahydropyranyl, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C _1-3 group, an OCF ₃ group, a NO 2 group, a CN group, a COOMe group, a CONH2 group, a COMe group, an OH group, an alkyl group having 1, 2, 3 or 4 carbon atoms; groups having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ² is H or alkyl having 1 or 2 carbon atoms;

R ³ is an alkyl group having 3, 4 or 5 carbon atoms, a phenyl group wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a CF ₃ group, OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, bromine, CF ₃ , OCF ₃ , OCHF ₂ , NO ₂ , CN, COOMe, CONH _2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

as well as their pharmaceutically acceptable salts.

Particularly preferred are compounds of formula I wherein

R ¹ is a group

R ⁹ R ¹⁰

R / X / R ¹¹

N 7 \ E H

A is -C _n H _2n -;

n is 0, 1 or 2;

O is an oxygen atom;

E is -C _m H _2m -;

m is 0 or 1;

R ⁸ is a hydrogen atom mama carbon; or alkyl group with 1, 2, 3 or 4 ató- R ⁹ is a hydrogen atom mama carbon; or alkyl group with 1, 2, 3 or 4 ató- R ¹⁰ is a hydrogen atom or alkyl group with 1 or 2 carbon

alkyl;

R ¹¹ is phenyl, wherein the phenyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , OCF ₃ , CN, COMe, OH, alkyl 1, 2, 3 or 4 carbon atoms, 1, 2, 3 or 4 carbon alkoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ² is H;

R ³ is an alkyl group having 3, 4 or 5 carbon atoms, a phenyl group wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, an OCF ₃ group, COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino ;

R ⁴ , R ⁵ , R ⁵ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, CF ₃ , OCF ₃ , CN, COOMe, CONH ₂ , COMe, OH, alkyl C 1, 2, 3 or 4 carbon atoms, C 1, 2, 3 or 4 alkoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

as well as their pharmaceutically acceptable salts.

Also particularly preferred are compounds of formula I wherein R ¹ is a group

R ^{8 R 9} / ^{R 12 R} XX _X D

N ^ A

Ά is -C _n H _2n - ·;

n is 0, 1 or 2;

D is a bond or an oxygen atom;

E is -C _m H _2m ^- ;

m is 0 or 1;

R ⁸ is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

R ⁹ is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

R ¹¹ is phenyl or pyridyl, wherein the phenyl or pyridyl is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , OCF ₃ , CN, COMe OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹² is alkyl having 1, 2, 3 or 4 carbon atoms or cyclopropyl;

R ² is H;

R ³ is an alkyl group having 3, 4 or 5 carbon atoms, a phenyl group wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, an OCF ₃ group, COOMe, CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, CF ₃ , OCF ₃ , CN, COOMe, CONH ₂ , COMe, OH, alkyl C 1, 2, 3 or 4 carbon atoms, C 1, 2, 3 or 4 alkoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

as well as their pharmaceutically acceptable salts.

Very particularly preferred are further compounds of formula I wherein

R ¹ is a group 13

R ⁹ . R ¹⁰ χ-X

N A E

A is -C _n H _2n -;

n is 0, 1 or 2;

D is a bond or an oxygen atom;

E is -C _m H _2m -;

m is 0 or 1;

R ⁹ is an atom alkyl; hydrogen or alkyl skupina s 1 or 2 carbon R ¹⁰ is an atom alkyl; hydrogen or alkyl skupina s 1 or 2 carbon R ¹¹ is a cycloalkyl group having 3, phenyl group, 4, 5 or 6 carbon alkyl,

wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, an OCF ₃ group, a CN group, a COMe group, an OH group, an alkyl group having 1, 2, 3 or 4 carbon atoms, alkoxy of 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹³ is C _p H _2p -R ¹⁴ ';

p is 0, 1, 2, 3 or 4;

R ¹ '' · 'is an aryl or heteroaryl group, wherein the aryl group and the heteroaryl group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, an OCF ₃ group, CN, COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

R ² is H;

R ³ is an alkyl group having 3, 4 or 5 carbon atoms, a phenyl group wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, an OCF ₃ group, COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino groups;

R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, CF ₃ , OCF ₃ , CN, COOMe, CONH ₂ , COMe, OH, alkyl C 1, 2, 3 or 4 carbon atoms, C 1, 2, 3 or 4 alkoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

as well as their pharmaceutically acceptable salts.

The alkyl groups and the alkylene groups may be unbranched or branched. The same applies to the alkylene radicals of formula _CnH2n, C H _{2 m,} and _m C _p H _2p. Alkyl groups and alkylene groups can also be unbranched or branched when substituted or when contained in other groups, for example in an alkoxy group or in a fluorinated alkyl group. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl group, 3,3-dimethylbutyl group, heptyl group. Derivatives derived from these groups are, for example, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 1,3 -propylene, 1,1-butylene, 1,4-butylene, 1,5-pentylene, 2,2-dimethyl-1,3-propylene, 1,6-hexylene, etc. are examples of alkylene groups.

Cycloalkyl groups can also be branched. Examples of C 3 -C 7 cycloalkyl are cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2-methylcyclobutyl, 3-methylcyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl , 3-methylcyclohexyl, 4-methylcyclohexyl, cycloheptyl, etc.

Heteroaryl groups are especially 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3- , 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl , 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-,

4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-oxadiazole- 2- or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1, 2,4-thiadiazol-3 or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5- benzimidazolyl, 1-, 3-, 4-,

5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7 - or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl.

Also included are the corresponding N-oxides of these compounds, thus also, for example, the 1-oxy-2-, -3- or -4-pyridyl group.

Particularly preferred heteroaromatic groups are thienyl, furyl, pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

Pyridyl means 2-, 3- and 4-pyridyl, thienyl 2- and 3-thienyl, and furyl both 2- and 3-furyl.

Aryl is phenyl or 2-naphthyl or 3-naphthyl.

Monosubstituted phenyl groups may be substituted in the 2, 3 or 4 position, disubstituted phenyl groups in the position

2,3, 2,4, 2,5, 2,6, 3,4 or 3,5, trisubstituted phenyl groups in the 2,3,4, 2,3,5, 2,3,6, 2 position, 4,5, 2,4,6 or in semi-heel 3,4,5. The same applies analogously to nitrogen heteroaromatics, naphthyl, thienyl or furyl groups.

When the group is substituted two or three times, the substituents may be the same or different.

When the compounds of formula I contain one or more acidic or basic groups, or one or more basic heterocycles, the invention also includes their corresponding physiologically or toxicologically acceptable salts. Thus, compounds of formula I containing, for example, one or more COOH groups can be used, for example, as alkali metal salts, for example sodium or potassium salts, or as alkaline earth metal salts, for example calcium or magnesium salts, or as ammonium salts, for example, salts with ammonia or organic amines or amino acids. The compounds of formula I wherein R ² is H, as best features deprotonation of the sulfonamide to form the sodium salt. Compounds of formula I containing one or more basic, i.e., protonable, groups or containing one or more basic heterocyclic rings may also be used in the form of their physiologically acceptable addition salts with inorganic and organic acids, for example, as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malate, gluconates, etc. If the compounds of the formula I contain both acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned above, internal salts, so-called. betaines. Salts may be obtained from the compounds of formula I by conventional methods, for example by reaction with an acid or base in a solvent or dispersant, or else from other salts by anion exchange.

The compounds of formula (I) may exist in stereoisomeric forms with appropriate substitution. If the compounds of formula I contain one or more centers of asymmetry, then these centers may independently have the configuration

The invention includes all possible stereoisomers, for example enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, for example enantiomers and / or diastereoisomers, in any ratios. For example, the invention relates to enantiomers in enantiomerically pure forms, i.e. both levorotatory and dextrorotatory antipodes, and also in the form of mixtures of the two enantiomers in different proportions or in the form of racemates. The individual stereoisomers may be prepared as desired by resolution of the mixture using conventional methods or, for example, by stereoselective synthesis. In the presence of mobile hydrogen atoms, the present invention also includes all tautomeric forms of the compounds of formula I.

The compounds of formula (I) are available by a variety of chemical processes, some of which are exemplified in Scheme 1 or Scheme 2. The substituents R ¹ to R ⁷ used in the schemes are as previously defined.

According to Scheme 1, the compounds of the invention can be prepared, for example, by first treating an aminocarboxylic acid of formula II in the presence of a base with a sulfonyl chloride of formula R ³ -SO ₂ -C1 or a sulfonic anhydride in a solvent such as water, pyridine or ether. . Suitable bases are inorganic bases such as sodium carbonate or potassium hydroxide, or organic bases such as pyridine or triethylamine.

The obtained sulfonylaminocarboxylic acid of the formula III can then be activated to the acid chloride, for example by treatment with a chlorinating agent such as phosphorus pentachloride, phosphorus oxychloride or. thionyl chloride in an inert solvent, and then reacted with an amine of formula HR ¹ to give the final compound of formula I. However, the activation of the carboxyl group in the compound of formula III can also be effected by other means, for example one of many methods commonly used by one of ordinary skill in the art. in peptide chemistry for coupling of amido-25 bonds, for example by conversion to a mixed anhydride or an activated ester using a carbodiimide such as dicyclohexylcarbodiimide.

The reaction of the activated sulfonylaminocarboxylic acid with an amine of formula HR ¹ is preferably carried out in an inert solvent such as pyridine, tetrahydrofuran or toluene, without or with the addition of an inert auxiliary base such as a tertiary amine or pyridine.

II

III

Scheme 1

Alternatively, according to Scheme 2, anhydrides of formula IV can be reacted beforehand with an amine of formula HR ¹ to form an o-aminobenzamide of formula VII, from which by reaction with sulfonic acid chloride of formula R ³ SC> 2C1 a compound of formula I is obtained. Intermediates of formula VII wherein R ² is hydrogen is amidation of o-nitrobenzoic acid of formula V with an amine of formula HNR ^X R ² and subsequent reduction of the nitro group to the amine.

Scheme 2

In all processes, it may be appropriate to temporarily protect the functional groups in the molecule at certain reaction stages. The technique of such protection is common to the skilled person. The choice of a protecting group for a given function and methods for its introduction and cleavage are described in the literature and can be adapted to the case without difficulty.

Thus, the compounds of the formula I according to the invention and their physiologically acceptable salts can be used in animals, in particular in mammals and in particular in humans, as medicaments, alone, in mixtures with one another or in the form of pharmaceutical preparations.

The present invention also relates to compounds of formula I and their physiologically acceptable salts for use as medicaments, their use in the therapy and prophylaxis of said diseases, and their use in the preparation of medicaments against these diseases and medicaments with K ⁺ channel blocking activity. Further, the present invention encompasses pharmaceutical compositions comprising, as an active ingredient, an effective dose of at least one compound of formula (I) and / or a physiologically acceptable salt thereof, in addition to conventional non-toxic carriers and excipients. The pharmaceutical compositions usually contain from 0.1 to 90% by weight of the compounds of the formula I and / or their physiologically acceptable salts. The pharmaceutical compositions may be prepared in a manner known per se. To this end, the compounds of the formula I and / or their physiologically acceptable salts are admixed with one or more solid or liquid galenic carriers and / or auxiliaries and, if appropriate, in combination with other substances having a therapeutic effect, a suitable dosage or dosage form is prepared, which can then be used as a medicine in human or veterinary medicine.

The medicaments containing the compounds of formula I and / or their physiologically acceptable salts according to the invention can be administered orally, parenterally, for example intravenously, rectally, by inhalation or topically, the preferred form of administration depending on the particular case, for example the symptoms of the disease being treated.

The choice of excipients suitable for the desired drug formulation is routine to the skilled artisan based on his experience. In addition to solvents, gelling agents, suppository bases, tabletting agents and other active compound carriers, for example, antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers, depotants, buffers or colorants can be used.

In order to obtain a beneficial therapeutic effect, the compounds of formula (I) may also be combined with other therapeutic agents. Thus, in the treatment of cardiac circulatory system disorders, preferred combinations with agents active against these disorders are possible. Preferred combination partners include, for example, other antiarrhythmic agents, i.e. class I antiarrhythmics, II. class III or III. class, such as blockers of _the IC or IK _r The conduit The conduit, e.g., dofetilide, or furthermore hypotensive substances such as ACE inhibitors (for example enalapril, captopril, ramipril), angiotensin antagonists, K 'activator-channel blockers, and the - and β-receptors, but also compounds with sympathomimetic and adrenergic activity, as well as Na ⁺ / H ⁺ exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other substances with a positive inotropic effect, such as digitalis glycosides or diuretics.

For an oral dosage form, the active compounds are mixed with suitable excipients such as carriers, stabilizers or inert diluents, and suitable dosage forms such as tablets, dragees, push-fit capsules, or aqueous, alcoholic or oily solutions are prepared by conventional methods. As inert carriers, for example, gum arabic, magnesium, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular corn starch, can be used. In this case, the preparation can be carried out using both dry and wet granules. Suitable oily carriers or solvents are, for example, vegetable or animal oils such as sunflower oil or fish oil. As solvents for aqueous or alcoholic solutions, for example, water, ethanol or sugar solutions or mixtures thereof can be used. Other excipients suitable for other dosage forms are, for example, polyethylene glycols and polypropylene glycols.

For subcutaneous or intravenous administration, the active compounds and, if desired, substances customary for this purpose, such as solubilizers, emulsifiers or other excipients, are converted into a solution, suspension or emulsion. The compounds of formula I and their physiologically acceptable salts can also be lyophilized and the lyophilizates obtained used, for example, for the preparation of preparations for injection or infusion. Suitable solvents are, for example, water, physiological sodium chloride solutions or alcohols, for example ethanol, propanol, glycerine, and in addition also sugar solutions such as glucose or mannitol, but also mixtures of the various solvents mentioned.

Suitable pharmaceutical formulations for application in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compounds of the formula I or their physiologically acceptable salts in a pharmaceutically acceptable solvent, in particular ethanol or water, or in a mixture of such solvents. If desired, the formulation may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, as well as a propellant. Such a formulation usually contains the active ingredient in a concentration of about 0.1 to 10%, in particular about 0.3 to 3% by weight.

The dosage of the active compound of the formula I administered or of its physiologically acceptable salts depends on the individual case and, as usual, must be adapted to the circumstances. Thus, it naturally depends on the frequency of administration and the efficacy and duration of action of the compounds used for therapy or prophylaxis, but also on the type and severity of the disease being treated, as well as the sex, age, weight and individual response of the human or animal being treated. whether it is treatment or prophylaxis. A typical daily dose of a compound of formula I when administered to a patient weighing about 75 kg is 0.001 mg / kg body weight to 100 mg / kg body weight, preferably 0.01 mg / kg body weight to 20 mg / kg body weight. The dose may be administered in the form of a single dose or may be divided into several, for example, two, three or four individual doses. Particularly in the treatment of acute cases of cardiac rhythm disorders, for example in an intensive care unit, parenteral administration by injection or infusion, for example long-term intravenous infusion, may also be advantageous.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations used:

DMAP 4-dimethylaminopyridine,

EDAC N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride, HOBT 1-hydroxy-1 H -benzotriazole.

General Regulation 1

Conversion of anthranilic acids to o-sulfonylaminobenzic acids by reaction with sulfonyl chlorides (analogous to Organic Syntheses 1952, 32, 8)

To a solution of 260 g (2.4 mol) of sodium carbonate and 1 mol of the appropriate anthranilic acid in 1.5 l of water at ^60-C was added in portions of 1.2 mmol of the corresponding sulfonyl chloride. The reaction mixture is heated to 60-80 ° C until complete (about 1-6 hours), with additional sulfonyl chloride added as necessary. After cooling, the reaction mixture is poured into 500 ml of 6 molar hydrochloric acid and the precipitated precipitate is filtered off with suction and dried at 45 ° C in a vacuum oven. If the product does not fall out in crystalline form, it is isolated by extraction into ethyl acetate.

Predstupeň la

2- (Toluene-4-sulfonylamino) benzoic acid

OH

NH

ABOUT:

According to general formula 1, 9.6 g of the title compound was obtained as a white solid from 6.85 g of anthranilic acid and 10.5 g of p-toluenesulfonyl chloride. MS (ES): 293 (M + 1).

Precedence lb

2-Butylsulfonylamino-5-methylbenzoic acid

ABOUT

ABOUT

According to general formula 1, 4.2 g of 2-butylsulfonylamino-5-methylbenzoic acid are obtained from 5 g of 5-methylanthranilic acid and 6.2 g of 2-butanesulphonyl chloride. MS (ES) 272 (M + 1).

Precedence lc

2- (4-Methoxybenzenesulfonylamino) -6-methylbenzoic acid

According to general formula 1, 1.6 g of the title compound are obtained in the form of a viscous oil from 1.6 g of 6-methylanthranilic acid and 2.3 g of 4-methoxybenzenesulfonyl chloride.

MS (ES): 323 (M + 1).

According to General Regulation 1, the following additional steps are synthesized, inter alia, in the following table:

precursor structure Mass (ES) 2 d 0 whether 312 (M + 2) 1 e 0 ^ oh y n ^of a 326 (M + 2) 1 f 'iX' ^B ° 'U. 320 (M + 1) 1 g 0 j ^ VOK M 306 (M + 1)

1 h I ⁰ ΓΓ ^ Ύ ^ ^0Η 306 (M + 1) 1 i 0 (Γ ^ ι ^ ^{σ Η} M I 308 (M + 2) 1 j 0 on p ^ 0 - ' 278 (M + 2) 1 k ^Cl 0 '-' 326 (M + 2) 1 l XÔ ' ^N ' ^H _ / = \ ^o f ~ W 312 (M + 2)

2 m XX • X 0 '- ^f 326 (M + 2) 1 n XC '4X 0 ^λ ' 292 (M + 2) 1 o X ^H / = \ v 322 (M + 2) 1 P _ä9 + —o 378 (M + 1) 1 q ^c 'OO ^0H ^ lyj ~ Q \ 356 (M + 1)

1 y Q ¹ T ^N ' ^H _ / = \ M 0- 322 (M + 2) 1 sec 0 ° C ^ ^0H ° 4-Q o- ' 322 (M + 2) 1 t XC 0 \ 352 (M + 1) 1 u XČ “0 ^X 272 (M + 2)

General Regulation

Conversion of sulfonylaminobenzoic acids to the corresponding acid chlorides

A) By the action of phosphorus pentachloride

To a suspension of 8 mmol of sulfonylaminobenzoic acid in 15 ml of dry toluene at room temperature was slowly added 9.6 mmol of phosphorus pentachloride. The mixture was stirred at 50 ° C for 3 hours, then cooled to 0 ° C, the acid chloride was filtered off with suction, washed with some toluene and dried at 45 ° C in a vacuum oven.

Pre-stage 2a

2- (4-toluenesulfonylamino) benzoyl chloride

Starting from 9.6 g of 2- (toluene-4-sulfonylamino) benzoic acid (precursor 1a) and 8.3 g of phosphorus pentachloride, 7.5 g of the title compound are obtained as a white solid.

MS (ES, detected as methyl ester after addition of methanol): 306 (M + 1).

B) With thionyl chloride mmol of sulfonylaminobenzoic acid was heated with 6 ml of thionyl chloride at 60 ° C for 3 hours, the reaction mixture was evaporated and the residue was evaporated twice with toluene.

Pre-stage 2b

2- (4-Methoxybenzenesulfonylamino) benzoic acid chloride

2.2 g of the title compound are obtained from 2.4 g of 2- (4-methoxybenzenesulfonylamino) benzoic acid and 5 ml of thionyl chloride.

MS (ES, detected as methanol after addition of methanol); 322 (M + 1).

According to general rule 2 (variant A or B), the following additional steps are prepared, inter alia, in the following table:

precursor structure Mass (ES after addition of methanol to acid chloride) Detection of the methyl ester 2c 0 cč 326 (M + 2) 2d 0 340 (M + 1) 2e e ....... 324 (M + 1) 2f 320 (M + 2)

2 g and 'c 320 (M + 2) 2 h A M 1 336 (M + 1) 2 i 0 pA, ^ν \ ^η / = λ λ? about -' 292 (M + 2) 2J A 1 ^H _ / = \ _ vvr \ J- * 0 '-' 340 (M + 1) 2 k TČ 0 - ' 326 (M + 2)

21 0 340 (M + 1) Ί rr ^C1 Ο'ιιΛ / 0 '-' 2 m x 0 WHAT 306 (M + 1) 2n with 0 ^C1 .Ka0 ^x - ' 336 (M + 1) 2o with 0 oO / = \ F ^> - F F 390 (M + 1) 2p ^C K oL 0 \ 370 (M + 1)

2q // 336 (M + 1) about about- 2 y 0 IY ° -H ABOUT 336 (M + 1) 2s IN" D ο- Χ 367 (M + 1) 2 t IIE 0 286 (M + 2) 2u rč \ ° // 0 286 (M + 2)

General Regulation 3A

Preparation of secondary amines by reductive amination

The primary amine (0.18 mmol) is dissolved in methanol (200 ml), aldehyde (0.09 mmol), sodium cyanoborohydride (0.18 mmol) and glacial acetic acid (0.18 mmol) are added and the mixture is stirred at room temperature for 6 hours. The mixture was concentrated, taken up in ethyl acetate and washed twice with sodium bicarbonate solution. The organic phase is concentrated and the residue is distilled under high vacuum. In the case of low volatile secondary amines, the volatiles are distilled off, the residue is dissolved from ether-tetrahydrofuran, ethereal hydrochloric acid is added and the precipitated hydrochloride is filtered off with suction, washed with ether and dried. The secondary amines obtained are used without further purification for reactions with sulfonylaminobenzoyl chlorides or sulfonylaminobenzoic acids.

Pre-step 3a

Benzyl- (1-methyl-1H-imidazol-2-ylmethyl) amine

As a general rule, 20.5 g of hydrochloride are obtained by reacting 19.4 g of benzylamine with 10 g of 2-formyl-1-methylimidazole. MS (ES +): mlz = 202 (M + 1).

Pre-stage 3b

Benzyl-pyridin-3-ylmethyl-amine

As a general rule, a secondary amine (2.8 g) was obtained from 4.32 g of 3-pyridylmethylamine and 2.12 g of benzaldehyde after kugelrohr distillation (0.1 mbar, 130 ° C).

MS (ES +): mlz = 199 (M + 1).

Pre-stage 3c

Benzyl (3-imidazol-l-yl-propyl) -amine

According to the general formula, a secondary amine (3.5 g) was obtained from 12.5 g of 3-imidazol-1-ylpropylamine and 5.3 g of benzaldehyde after kugelrohr distillation (0.1 mbar, 130 ° C).

MS (ES +): mlz = 216 (M + 1).

According to General Regulation 3B, further pre-stages are prepared, which are listed in the following table:

precursor structure mass 3d 188 (M + 2) 3e 200 (M + 1) 3f ΧΌ 205 (M + 1) 3 g XX 202 (M + 2) 3h 238 (M + 2) 3 i 162 (M + 2) 3J X ^ N 163 (M + 2)

3 k α H 177 (M + 2) 3o you a. 231 (M + 2) 3p \ / N. II H 214 (M + 2) 3q σ 211 (M + 2) 3r lake 200 (M + 1)

General Regulation 3B

Preparation of α-branched amines from ketones

To a solution of 200 mmol of hydroxylammonium chloride and 200 mmol of sodium acetate in 120 ml of water, a solution of 67 mmol of the corresponding ketone in 120 ml of ethanol is added at 30 ° C and the mixture is heated to 60 ° C until complete (1 to 3 hours). After cooling, the reaction mixture is diluted with water and the precipitated oxime is suctioned off or, if necessary, isolated by extraction. The product obtained is dissolved in 100 ml of methanol, 100 ml of tetrahydrofuran and 10 ml of concentrated ammonia solution and subjected to hydrogenation on Raney nickel at room temperature and atmospheric pressure until absorption of hydrogen ceases. After filtering off the catalyst and concentrating the reaction mixture, the corresponding amine is obtained, which is purified by chromatography if necessary.

Pre-stage 3 1

1-Benzylpropylamín

According to general formula 3B, 4.5 g of the title compound is obtained from 10 g of 1-phenyl-2-butanone.

Pre-step 3 m 1-Pyridin-4-ylpropylamine

According to general formula 3B, 10.2 g of the title compound are obtained from 10 g of 4-propionylpyridine.

Pre-step 3 n 1-Pyridin-3-ylpropylamine

According to general procedure 3 B, 0.9 g of the title compound is obtained from 1 g of 3-propionylpyridine.

Pre-step 3 sec

1-Cyclopropyl-1-phenylmethylamine hydrochloride

a) N- (cyclopropylphenylmethyl) formamicl

A mixture of 14.8 g (0.1 mol) of cyclopropylphenyl ketone, 11.4 ml (0.3 mol) of formic acid and 20 ml (0.5 mol) of formamide was heated at 160 ° C for 18 hours. After cooling, 100 ml of water are added to the reaction mixture and extracted twice with 50 ml of ether each time. The ethereal phase is washed with 50 ml of 10% sodium carbonate solution, dried over sodium sulphate and concentrated. 13.6 g (77.4 mmol) of a yellow oil are obtained.

b) 1-Cyclopropyl-1-phenylmethylamine hydrochloride

13.6 g (77.4 mmol) of N- (cyclopropylphenylmethyl) formamide (see a) are refluxed with 100 ml of 2N HCl for 18 hours. After cooling, the mixture is extracted twice with 50 ml of dichloromethane each and the aqueous phase is concentrated. The residue is taken up in 30 ml of 2-propanol, heated to boiling and left in the refrigerator overnight. The precipitated crystals of 1-cyclopropyl-1-phenylmethylamine hydrochloride (3.85 g, 21 mmol) are filtered off with suction and dried in a vacuum oven.

Pre-stage 3 t

Cyclopropylpyridin-2-ylmethylamine hydrochloride

a) Cyclopropylpyridin-2-ylmethyleneamine

A solution of 25 g (157.5 mmol) of 2-bromopyridine in 100 ml of diethyl ether was added dropwise over 20 minutes to a solution of n-butyllithium (100 ml, 160 mmol) in diethyl ether (300 ml). The dark red solution was stirred for 5 hours and then 8.8 g (131 mmol) of cyclopropanecarboxylic acid nitrile in 100 mL of ether was added. The mixture was stirred at -70 ° C for 30 minutes, warmed to room temperature and stirred for an additional 30 minutes. Then 15 g of Na ₂ SO ₄ .10H ₂ O are added and stirred for one more hour. To the red solution was added Na ₂ SO ₄ , filtered and concentrated. The residue is subjected to kugelrohr distillation and the product is boiled at 75-120 ° C / 0.3mbar.

This gave 18.6 g (127 mmol); stored at -18 ° C.

light yellow oil that is

b) Cyclopropylpyridin-2-ylmethylamine hydrochloride

2.72 g (18.6 mmol) of cyclopropylpyridin-2-ylmethyleneamine (see Experiment a) are dissolved in 35 ml of dry methanol. At 0 ° C, 0.69 g (18.6 mmol) of NaBH _{4 is} added portionwise, the mixture is stirred for 30 minutes at 0 ° C, 2 hours at room temperature, then adjusted to pH 3 by addition of 1M HCl, the methanol is evaporated. on a rotary evaporator and the residue lyophilized. 8.8 g of cyclopropyl-pyridin-2-ylmethylamine hydrochloride are obtained in admixture with inorganic salts and boric acid.

Pre-stage 3 u

Cyclopropylpyridin-3-ylmethylamine hydrochloride

a) Cyclopropylpyridin-3-ylmethyleneamine

According to the 3-step precaution, from 8.8 g (131 mmol) of cyclopropanecarboxylic acid nitrile, 25 g (157.5 mmol) of 3-bromo-47 pyridine and 173 mmol of n-butyllithium solution after kugelrohr distillation (130 ° C / 0.2 mbar) to give 7.5 g (51 mmol) of imine as a yellow oil.

b) Cyclopropylpyridin-3-ylmethylamine hydrochloride

According to the 3p precursor procedure, 16.6 g of cyclopropylpyridin-3-ylmethylamine hydrochloride are obtained in a mixture of 7.5 g (51.5 mmol) of imine (see experiment a) and 1.9 g (51.4 mmol) of NaBH ₄ . with inorganic salts and boric acid.

Pre-stage 3 v

1- (5-Methyl-furan-2-yl) propylamine

To a mixture of 5 g (36 mmol) of 2-methyl-5-propionylfuran and 28.2 g (366 mmol) of ammonium acetate in 300 ml of methanol is added portionwise with stirring 11.35 g (180 mmol) of sodium cyanoborohydride and the mixture is left to stand. React for 18 hours at room temperature. The mixture is then concentrated, 200 ml of dichloromethane are added and the organic phase is washed three times with 50 ml of sodium bicarbonate solution each, dried over sodium sulphate and concentrated. 3.9 g (28 mmol) of amine are obtained in the form of a pale yellow oil.

Pre-stage 3 w

1-Phenylprop-2-ynylamine hydrochloride h ₂ n

II

The compound is prepared as described (Bjorn M., Nilsson et al., J. Heterocycl. Chem. (1989), 26 (2), 269-275) by a Ritter reaction starting from 1-phenyl-2-propynyl alcohol followed by hydrolysis with hydrochloric acid. .

Pre-stage 3 x

C-Cyclopropyl-C- (6-methoxypyridin-2-yl) methylamine

a) Cyclopropanecarbaldehyde-O-benzyloxime

A mixture of cyclopropanecarbaldehyde (6.7 g, 95.6 mmol), O-benzylhydroxylamine (15.3 g, 95.6 mmol), sodium acetate (15.7 g, 191.2 mmol) and ethanol (250 ml) was stirred at room temperature for 18 hours. . The reaction mixture was then concentrated and Na ₂ SO ₄ was added. The residue is extracted three times with 50 ml of dichloromethane each, the organic phase is concentrated and the crude product is purified by chromatography on silica gel. 5 g (28.6 mmol) of a colorless liquid are obtained.

b) O-Benzyl-N- [cyclopropyl- (6-methoxypyridin-2-yl) methyl] hydroxylamine

To 3.76 g (20 mmol) of 2-bromo-6-methoxy-pyridine in 20 mL of tetrahydrofuran at -78 ° C was added 8.8 mL (22 mmol) of a solution of n-butyllithium (2.5 M in toluene). After 30 minutes, the resulting dark red solution was added to a solution of 1.4 g (8 mmol) of cyclopropanecarbaldehyde-O-benzyloxime (see experiment a) and 2.52 ml (20 mmol) of boron trifluoride etherate in 40 ml of toluene, which was stirred for 15 min. minutes at -78 ° C. The reaction mixture was stirred at -78 ° C for 4 hours, then slowly warmed to room temperature, quenched with water and basified with saturated Na ₂ CO ₃ solution. The organic phase is separated, the aqueous phase is extracted with toluene and the combined organic phases are dried over sodium sulphate. After evaporation of the solvent, the crude product is taken up in 12 ml of acetonitrile, the insolubles are separated and the product is isolated by preparative HPLC. Yield 650 mg of product as a red oil.

c) C-cyclopropyl-C- (6-methoxypyridin-2-yl) methylamine

650 mg (2.3 mmol) of O-benzyl-N- [cyclopropyl- (6-methoxy-pyridin-2-yl) -methyl] -hydroxylamine (see Experiment b) was dissolved in 18 ml of glacial acetic acid and the solution was diluted with 18 ml of water. 3.3 g of zinc dust are added and the suspension is reacted in an ultrasonic bath for 24 hours. The mixture was filtered through diatomaceous earth, which was then washed with dilute (1: 1) acetic acid. The filtrate was partially evaporated, adjusted to pH 11 by addition of saturated Na 2 CO 3 solution, extracted three times with 100 ml of dichloromethane, dried over sodium sulfate and concentrated. 0.4 g (2.2 mmol) of product is obtained in the form of a dark red oil.

General Regulation

Preparation of 2-aminobenzoic acid amides from 2-nitrobenzoic acids

The corresponding 2-nitrobenzoic acid is first converted to the 2-nitrobenzoic acid amide by reaction with the amine according to General Rules 2 and 5. Then, the 2-nitrobenzoic acid amide (4 mmol) is hydrogenated in 50 ml of tetrahydrofuran and 50 ml of methanol in the presence of 10 ml. % palladium on carbon (spatula tip) at room temperature and atmospheric pressure. The catalyst is filtered off with suction and the filtrate is concentrated to give the corresponding 2-aminobenzoic acid amide.

In this way, the following pre-stage is also synthesized:

precursor structure mass 4 a .0 320 (M + 1)

General Regulation 4 B

Preparation of 2-aminobenzoic acid amides from isatinic anhydride

A solution of 20 mmol of isatinic anhydride and 22 mmol of the corresponding amine in 75 ml of dimethylformamide is heated to 60 ° C until complete reaction. The reaction mixture is quenched with 100 ml of water and the product is filtered off with suction or isolated by extraction.

Step 4b (S) -2-Amino-N- (1-phenylpropyl) benzamide

According to general formula 4b, 3.4 g of the title compound are obtained after 3 hours at 60 ° C from 3 g of (S) -1-phenylpropylamine and 3.2 g of isatinic anhydride.

General Regulation

Reaction of sulfonylaminobenzoyl chlorides with amines

To a solution of the amine (0.66 mmol) and trierylamine (0.9 mmol) in methylene chloride (3 mL) was added the corresponding sulfonyl 51 aminobenzoyl chloride (0.6 mmol). The reaction mixture was stirred overnight at room temperature and diluted with 5 mL of water and 10 mL of methylene chloride. The organic phase is washed with 1 M hydrochloric acid and then with saturated sodium bicarbonate solution. After drying over magnesium sulphate, it is concentrated in vacuo and, if necessary, the product is purified by preparative HPLC or column chromatography.

Example 1 (S) -2-Phenylsulfonylamino-5-chloro-N- (1-phenylethyl) benzamide

O i

Cl

NH

O = S = O

According to general formula 5, 61 mg of the title compound were obtained from 2-phenylsulfonylamino-5-chlorobenzoyl chloride and (S) - (-) - 1-methylbenzylamine.

MS (ES < + >): m / z = 415 (M + 1).

Example 2 (R) -2-Phenylsulfonylamino-5-chloro-N- (1-phenylethyl) benzamide

ABOUT

Cl

NH

I

O = S = O

According to general formula 5, 160 mg of the title compound were obtained from 2-phenylsulfonylamino-5-chlorobenzoyl chloride and (R) - (+) - 1-methylbenzylamine.

MS (ES < + >): m / z = 415 (M + 1).

Example 3 (S) -2-phenylsulfonylamino-5-chloro-N- (1-phenylpropyl) benzamide

s = o = o

According to general formula 5, 140 mg of the title compound were obtained from 2-phenylsulfonylamino-5-chlorobenzoyl chloride and (S) - (-) - 1-ethylbenzylamine.

MS (E +): m / z = 429 (M + 1).

Example 4 (R) -2-Phenylsulfonylamino-5-chloro-N- (1-phenylpropyl) benzamide

s = o = o

According to general formula 5, 130 mg of the title compound were obtained from 2-phenylsulfonylamino-5-chlorobenzoyl chloride and (S) - (-) - 1-ethylbenzylamine.

MS (ES +): mlz = 429 (M + 1).

Example 5 (S) -2-Phenylsulfonylamino-5-chloro-N- [1- (4-methoxyphenyl) ethyl] benzamide

s = o = o

According to general formula 5, 136 mg of the title compound were obtained from 2-phenylsulfonylamino-5-chlorobenzoyl chloride and (S) - (-) - 1- (4-methoxyphenyl) ethylamine.

MS (ES +): mlz = 445 (M + 1).

Example 6 (R) -2-phenylsulfonylamino-5-chloro-N- [1- (4-methoxyphenyl) ethyl] benzamide

According to general formula 5, 112 mg of the title compound was obtained from 2-phenylsulfonylamino-5-chlorobenzoyl chloride and (P) - (+) - 1- (4-methoxyphenyl) ethylamine.

MS (ES +): mlz = 445 (M + 1).

Example 7

2-Phenylsulfonylamino-5-chloro-N- (phenyl-pyridin-2-ylmethyl) -benzamide

According to general formula 5, 211 mg of the title compound were obtained from 2-phenylsulfonylamino-5-chlorobenzoyl chloride and C-phenyl-C-pyridin-2-ylmethylamine.

MS (ES +): mlz = 478 (M + 1).

Example 8

N-benzyl-N-pyridin-3-ylmethyl-2- (toluene-4-sulfonylamino) -benzamide

According to general formula 5, 1.1 g of the title compound are obtained from 0.93 g of 2-p-toluenesulfonylaminobenzoyl chloride and 0.65 g of benzylpyridin-3-ylmethylamine (precursor 3b). After addition of an ethereal HCl solution, the compound is isolated as a white salt.

MS (ES +): mlz = 472 (M + 1).

According to General Regulation 5, the following additional examples shall be prepared, inter alia:

Example structure Mass (ES) 9 CH, Ύ 425 (M + 2)

10 D Ya 442 (M + 1) 11 9 U ° '·. 421 (M + 1) I 12 9 ds ¹ '' AJ U ° 9 401 (M + 1); and | 1 s and 13 9 AyyAJ U ° i 387 (M + 2) 14 9 Y ry ^CH 'AY ° 392 (M + 1)

15 Π 419 (+ 1) ° γ ^Ν ' ^ ^ΟΗ 3γγΟΗ ₃ Λ -ν-Μ ⁰ 0 16 ς ° γ ^Ν · 435 (+ 1) χΑ ¹ 17 C ° γ ? · ^Ν {/ τ 393 (+ 1) X χΧ 18 C Ί 421 (+ 1) ° γ Τ .1+ .CH, ΑΑ X χΧ

19 A 425 (M + 2) • VxA ^Ν χ ^ · ° 1 N x o h ₃ c 20 χ, Ό 0 ^. <° AA Xx \ ^{h h} 3 h ₃ cn 353 (M + 1) 21 n «Ά ° A ch ₃ 372 (M + 1) 22 n CH ₃ Ν ' ^ζΑχχΧ A 1 o = s = o Φ C! 407 (M + 2)

26 9-A ° ^x ch ₃ \ / ^CH 3 y 439 (M + 1) 27 CH, 1 448 (M + 1) ° \ A H, C. Ά Y9 with ί ° U IN 1 <A ch ₃ 28 0 ch ₃ 394 (M + 1) y M CH ₃ 29 0 (A 488 (M + 1) <Γγ9 ^ Α AJ TX: «x oV | ch ₃ ch ₃

30 ^c c h ₃ c _n - <3 \ t'T 474 (M + 1) " 'I CH ₃ 31 478 (M + 1) ⁰ / ' ^XX ' N ^{/ _} U ^Xn Ύ ll ch ₃ 32 r * 488 (M + 1) T L N ^{/ X} - ^{/ X} 0 ABOUT ^ N rf U % ŕ ° ^N Ύ ll 'ch ₃ 33 F \ 473 (M + 1) 8 y J Α (χ- 'N IN y U ° O 's * I ch.

34 ° χχ 435 (M + 1) 35 L J ΗP ° «,« ° ^ X 511 (M + 1) 36 P S Γ X ° Δ 474 (M + 1) 37 Δ χΛ-Χ y P% * ° ~ x. 435 (M + 1)

38 . :. 462 (M + 1) <N I ⁰ and _o <° X 39 íí The 502 (M + 1) l! r ( x ° °: o <° R <\ X The I! 40 4-89 (M + 1) w > = N HgCl ^ [f ^Z Xr'N ^/ \ v // ° a <° ^^ CH ₃ 41 H ₃ C _X of ³ N K 505 (M + 1) CH, I The = N 0 UY 0 XCH _:

42 0 cc ° > ° X, 450 (M + 1) 43 Γ = \ o ^{N <} y ^N ^ cH ₃ 558 (M + 1) γΕ _Ν > to Λ Sč ^íl O = s = o ΐχΐ Λ Uy 4 44 ABOUT 492 (M + 2) S Ex ° «.« 0 ^{N N} hj 0 / b x 45 n 505 (M + 1) sEx ^C 'Xl U % «0 ^{N ×} » X EE CH,

46 ^F V ^ · u 490 (M + 1) X 'N Y 47 about 503 (M + 1) CH ₃ 50 ABOUT Α-Ά // -N at J ch ₃ 48 .s X Γ; 435 (M + 1) ABOUT ' ^X N ^' / ³ γ. IN CH ₃ 49 ₈ X n 450 (M + 1) ABOUT ^ ^Sx A A ⁿ at 0 50 about 487 (M + 1) A Q Υγγ y / -N M -about'"'

51 i Q < 452 (M + 1) X ? S ^H o = s = o> · about 52 G 0 ^: t n 5 G 400 (M + 1) 53 XJ < ^ NH 1 D = S = O X Ό 440 (M + 2)

General Regulation

Reaction of sulfonylaminobenzoic acids with amines

To a solution of 0.42 mmol of the appropriate sulfonylaminobenzoic acid, 0.44 mmol of HOBT and 0.44 mmol of EDAC in 5 mL of tetrahydrofuran at 0 ° C was added dropwise 0.44 mmol of the appropriate amine, and the mixture was stirred at room temperature for 4-12 hours. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and then with sodium bicarbonate solution. After drying over magnesium sulphate and concentration in vacuo, the corresponding amide is obtained which is purified by preparative HPLC if necessary.

Example 54

2- (Butylsulfonylamino) -N-cyclohexyl-5-methyl-benzamide

184 mg of the title compound is obtained from 200 mg of 2-butylsulfonylamino-5-methylbenzoic acid (precursor 1b) and cyclohexylamine according to general formula 6.

MS (ES +): mlz = 353 (M + 1).

According to general rule 6, the following examples are prepared:

Example structure mass 55 _Π Oc 1 o = s = o 375 (M + 2)

56 o! ro 1 δ 400 (M + 1) 57 oOOO ° t ° 403 (M + 1) 58 00¼ ° T ° 375 (M + 2)

General Regulation 7

Reaction of 2-aminobenzoic acid amides with sulfonyl chlorides

To a solution of 0.2 mmol of the appropriate 2-aminobenzoic acid amide (pre-step 4) and 0.6 mmol of pyridine in 5 mL of methylene chloride is added dropwise at 0 ° C a solution of 0.3 mmol of the corresponding sulfonyl chloride in 2 mL of methylene chloride. room temperature. The organic phase is washed with water, dilute hydrochloric acid and sodium bicarbonate solution and the crude product obtained is purified by preparative HPLC as necessary.

In this way, the following products are obtained, inter alia:

Example structure mass 59 o Ί 400 (M + 1) what s = o = o about. about 60 how much? s = o = o Ό 400 (M + 1) 61 x 0 = ^ 0 ABOUT 444 (M + 1) 62 o X Oô W ^ 'NH O = S = O xA? Ό 444 (M + 1)

63 ⁰ 0 425 (M + 2) 00 « NH O = S = O r '' O'o from 64 ⁰ Ô o = s = o x x ° Ό 425 (M + 2) 65 ⁰ OÔ NH O = zS = O / ^N x ΤΊ 487 (M + 1) 66 ⁰ 'o 00 o = s = o Φ cf ₃ FROM 462 (M + 1)

67 Ooide s = o = o Φ F, C '° 478 (M + 1) 68 Γ ^ί? 0Γ'Ν ' ^Λ > ^ ^ί: > Ί LI ^Η LJ o = s = o φ C! 429 (M + 1) 69 00 ΓΊ = ^ - ^ ΝΗ O = S = O about 394 (M + 1) 70 A qJ-J o _f 0 A 1 487 (M + 1)

71 -9 NH 438 (M + 1) 72 -9 CÔy, u == U ^c 487 (M + 1) 73 CC _H = 0 = S = 0 * Ί 361 (M + 1) 74 0 = S == 0 9 389 (M + 2)

75 Tjioe ά 473 (M + 1) 76 Ooy> 0 = S = 0 T ' 439 (M + 1) 77 σΤο s = o = o about 423 (M + 1)

The 3-methylbutylsulfonyl chloride required for Example 74 is prepared by reacting 3-methylbutylbromide with a solution of ammonium sulfite at reflux and the resulting sulfonic acid is chlorinated with phosphorus pentachloride to sulfonyl chloride.

In analogy to the above examples, using one or more of the general regulations 1-7, the following compounds are further prepared:

Example structure mass 78 o / ^{r ==} \ h XX 400 (M + 1) 79 A J J ⁰ * ^ ° 473 (M + 1) 80 H xl \ ^ «Oj 485 (M + 2) 81 ° / ί · _χ / x Jx lx — K \ T l JL% «° ^« XX 492 (M + 1) 82 IXO 05 ^ 0 464 (M + 1) 83 h J \ 474 (M + 1)

84 , Α pkkWj) ¢. / i v 477 (M + 1) 85 χΛκ hj% ° ° ^W IX 425 (M + 2) 86 Pz> XX] 1 -XX 460 (M + 1) 87 -¾ ^ 487 (M + 1) 88 > x CksííS ^» 502 (M + 1)

89 sp Ο-ΉΡ ,, ιΙ J J <w> ^N ^ n. 508 (M + 1) 90 | 0 439 (M + 1) O _v Άϊ ΊΛ NH | M ° A > 91 I 0 458 (M + 1) about. pT IIA NH AA | ° ίχ x 92 I 0 II p 452 (M + 1) o _v TYX Ά AA I U A and 93 I 0 Y 452 (M + 1) 0 A I 0 A and

94 CÔ u NH X 407 (M + 2) 95 X VXO XX · 431 (M + 1) 96 £ ·; 1 454 (M + 1) 97 Ay ° % Xh HN. / X 454 (M + 1) 98 $ 3 ^σ δ 394 (M + 1)

99 XX 439 (M + 1) 100 o = 3 o ^z 'of 17 U. 482 (M + 1) 101 44 fX JL.CX /) >θκ> ° ^ν · λ ^ x XX 505 (M + 1) 102 , 4 ^ ^ ΐχ 478 (M + 1) 103 Λ X-N N 1z jX a 439 (M + 1)

104 S.Φύ ° o ¹ · Ν Ν-χ Ό- · Λ F 442 (M + 1) 105 σ ^% í 394 (M + 1) 106 ^f y ^ AUxi UL ^H U = s = o 9 Cl 448 (M + 1) 107 δ XUP XX 511 (M + 1)

108 F Α- χ 497 (+ 1) 109 s Αχ Μ 493 (+ 1) 110 Αχ Αι ^Ν \ Α ΑΧ ° χΑ, 496 (+ 1) 111 αΑ ^ «ΧΧ 472 (Μ + 1) 112 ^ ΤΧ 461 (+ 1)

113 Π I 450 (M + 1) 114 ⁰ yy CU Ό - 1 389 (M + 2) 115 ^{F f} n o = s = o 427 (M + 1) 116 A 464 (M + 1)

According to General Regulation 5, the following additional examples are prepared:

Example structure Mass (ES) 117 op- 505 (M + 1) 118 X 486 (M + 1) 119 SrO CČV) 1 ^with XX 483 (M + 1) 120 ^ Lr ° 00 00 xx 480 (M + 2) 121 .χ> \ —C # xx 475 (M + 1)

122 465 (+ 1) ΝΗ W Ν-Λ IN) I X 123 453 (+ 1) η ρ / γ ΝΗ | c ^ ° H? 124 I Í? 452 (+ 1) Υνί | η ιΓ ^ ° ^N I X ll 125 0 402 (+ 1) Jχ Ν '1JL ^Η yo liy νΥ 126 0 ^ΎΥτ Ν ΕΛ Η ° Ύη 436 (+ 1) X. ι>

127 ⁰ Y 432 (M + 1) ΎγΥ LA ^H r Q about / 128 0 385 (M + 2) 'V ^ TN LA ^H O ^' O  " 129 ⁰ I 432 (M + 1) ltO'n ' ¹ LA ^H o' ^s ^ o ^ o— vZy ² 130 0 II i ___ 400 (M + 1) Γί NH | about ° A y

131 1 1 0th TJ ⁰ 1 1 ^Η ' ^χ ^ ^Χ ' ΝΗ 9χ ΎΊ 453 (M + 1) 9 sp N *. 132 0 Ζ9 402 (M + 1) Ί 1 ^Η I x) N 0 133 0 / f 440 (M + 2) π Vr I -IN °? 9 9 134 0 468 (M + 2) UL ^Η ΝΗ 1 L Ά N ° ΐΌ 9 ₀ \

135 0 x 442 (M + 1) C H Δη they 136 o < 392 (M + 1) about IX ^X NH | 0 -WITH. P

According to general regulation 6, the following additional examples are prepared:

Example structure Mass (ES) 137 0 ' n \ ογ Xp o - w = o 406 (M + 1)

138 ° PPfS s = o = o 404 (M + 2) 139 << X I o-p o = 470 (M + 2) 140 Q NH NH I <S <s o ^ after - 492 (M + 2)

141 Αν O'Y'O C 455 (M + 1) 142 G "Z / = \ ° ^ XvCX -about and 455 (M + 1) 143 '0 \ / T \ H ⁰ \ / ^N JL J 417 (M + 1) 144 XÔ u Λ 390 (M + 1)

According to General Regulation 7, the following additional examples are prepared:

Example structure Mass (ES) 146 YjAA by \ ¹ ° A ° ^r 377 (M + 2) 147 q Chiral ° 7 ° 377 (M + 2) 148 0 f 'Chiral 'XOX) Y 392 (M + 1)

149 ⁰ f r 'Chiral X) 392 (M + 1) \ about The ABOUT ^ NH delta-0 ° A 150 O f II The chiral 454 (M + 1) \ about Y rV Άη x 3 ° _S z ° 151 s f The chiral 454 (M + 1) C Y NH | 0 C ) = P = o I Λ YY Y / 0

Example 152

5-hydroxy-N- (1-phenylpropyl) -2- (toluene-4-sulfonylamino) -benzamide

The compound is obtained from Example 90 by cleavage of methyl ether with boron tribromide.

Pharmacological studies

Human Kv1.5-channels are expressed in Xenopus oocytes. To this end, oocytes from Xenopus laevis are first isolated and defoliated. RNA encoding the Kv1.5 synthesized in vitro is then injected into these oocytes. After 1 to 7 days expression of Kv1. The 5-protein is measured on the oocytes by Kv1.5-currents using a two-voltage electron-clamp technique. The Kv1.5 channels are usually activated by voltage jumps of 0 mV and 40 mV for 500 ms. The bath was washed with a solution of the following composition: NaCl 96 mM, 2 mM KCl, 1.8 mM CaCl ₂ , 1 mM MgCl ₂ , 5 mM HEPES (titrated with NaOH to pH 7.4). The experiments are carried out at room temperature. Data acquisition and analysis is performed using the following instruments: a Geneclamp amplifier (Axon Instruments, Foster City, USA) and a D / A converter and MacLab Software (AD Instruments, Castle Hill, Australia). The compounds of the invention are added to the bath at various concentrations in the assay. The effects of the compounds are calculated as the percentage inhibition of the control Kv1.5-current obtained when no compound is added to the solution. The data is then extrapolated using the Hill equation to determine the inhibitory concentration of IC ₅₀ for the compounds.

IC ₅₀ values for the following compounds are determined as follows:

Example # IC ₅₀ [μΜ] 1 5.5 2 8.2 3 2.8 4 4.1 5 4.5 6 8.2

7 5, 1 8 0.9 9 4.9 10 2.5 11 8.0 12 5.4 13 10,0 14 8.5 15 7.8 16 6.4 17 7.5 18 6.7 19 4.2 20 7.7 21 5.2 22 00 23 5, 0 24 3.0 25 3.4 26 0, 6 27 5, 6 28 3.2 29 5.1 30 0.7 31 2, 6 32 8.5 33 6, 5

34 3.1 35 2.0 36 2.0 37 1.9 38 1, β 39 > 10 40 0.8 41 1.9 42 5.0 43 5.4 44 2.9 45 2.5 46 1.2 47 4.7 48 > 10 49 6, 3 50 0.7 51 3.6 52 3.0 53 2.5 54 4.0 55 4.6 56 10,0 57 5.0 58 > 10 59 1.7 60 0.7

61 5, 6 62 3.5 63 1.7 64 0, 6 65 4.8 66 4.0 67 5, 8 68 2.9 69 1.3 70 3.8 71 6.9 72 5, 0 73 3.1 74 1.7 75 2.9 76 4.7 77 2, 6 78 2.7 79 0.7 80 1.2 81 0.4 82 3.2 83 1.9 84 1.0 85 5.2 86 1.8 87 6, 0

88 3.9 89 3.2 90 0, 5 91 Ο 00 92 0.9 93 1, i 94 ι, ο 95 0.7 96 ι, ο 97 0.9 98 2.0 99 0.9 100 1.6 101 0.9 102 0.7 103 1.4 104 ι, ο 105 2.6 106 3.8 107 0.9 108 1.2 109 I-1 , -ί 110 1.0 111 1.7 112 0.5 113 2.6 114 1.4

115 2.4 116 1.1 117 2, 4 118 2.2 119 2.7 120 1, 4 121 0, 6 122 1.2 123 2.9 124 ι, ο 125 1.8 126 0.6 127 3.3 128 2.2 129 1.3 130 0.7 131 0.7 132 1.0 133 1.4 134 0.9 135 1.2 136 0.9 137 2.4 138 1.8 139 1.0 140 1.4 141 1.1

142 0.7 143 3, 6 144 2.8 145 2.6 146 2.5 147 3, 8 148 2.1 149 2.2 150 0.3 151 1, 5 152 2, 6

Claims (15)

PATENT CLAIMS Compounds of formula I R .4 R 1 (I) is ^R 1 or NR A ABOUT D E A ABOUT D E is -C _n H _2n -; n is 0, 1, 2, 3, 4 or 5; is an oxygen atom; is a bond or an oxygen atom; It is -C _m H _{2 m} -; m is 0, 1, 2, 3, 4 or 5; is H, alkyl having 1, 2, 3 or 4 carbon atoms or C _p H _2p -R ^14; p is 0, 1, 2, 3, 4 or 5; R ¹⁴ is a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, an aryl group or a heteroaryl group, wherein the aryl and heteroaryl group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ⁹ is hydrogen or alkyl having 1, 2, 3, 4, 5 or 5 6 carbon atoms; R ¹⁰ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by 1 , 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH 2, COMe, NH ₂ OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, suifamoyl, methylsulfonyl and methylsulfonylamino; R ¹¹ is cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidyl, wherein the phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , the group N0 _2, CN, COMe, _NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl a methylsulfonylamino group; R ¹² is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ group, OCF ₃ group, NO ₂ group, CN group, COOMe group, CONH ₂ group, COMe group, NH ₂ group, OH group , alkyl group with 1, 2, 3 or 4 carbon atoms, an alkoxy group having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ¹³ is C _p H ₂ p R ¹⁴ '; p is 0, 1, 2, 3, 4 or 5; R ¹⁴ 'is cycloalkyl having 3, 4, 5 or 6 carbon atoms, tetrahydrofuranyl, tetrahydropyranyl, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, C 1 alkyl, 2, 3 or 4 carbon atoms, an alkoxy group having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ¹⁵ is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; R ² R ³ R ² R ³ is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; is alkyl having 3, 4, 5, 6 or 7 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl or naphthyl, the phenyl or naphthyl being unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ group, OCF ₃ group, NO ₂ group, CN group, COOMe group, CONH ₂ group, COMe group, NH ₂ group, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , OCHF ₂ , NO ₂ , CN, COOMe, _CONH2, COMe, _NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino ; as well as their pharmaceutically acceptable salts. Compounds of formula (I) according to claim 1 wherein u is or 101 A is -C _n H _2n -; n is 0, 1, 2, 3, 4 or 5; O is an oxygen atom; D is a bond or an oxygen atom; E is -C _m H _2m -; m is 0, 1, 2, 3, 4 or 5; R ⁸ is H, alkyl having 1, 2, 3 or 4 carbon atoms or C _p H _2p -R ^14; p is 0, 1, 2, 3, 4 or 5; R ¹⁴ is a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, an aryl group or a heteroaryl group, wherein the aryl and heteroaryl group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ⁹ is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; R ¹⁰ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by 1 , 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH groups ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ¹¹ j ^E cycloalkyl having 3, 4, 5 or 6 carbon atoms, phenyl or pyridyl, where phenyl and pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine , bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COMe, NH 2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ¹² is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ group, OCF ₃ group, NO ₂ group, CN group, COOMe group, CONH ₂ group, COMe group, NH ₂ group, OH group , alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ¹³ is C _p H _2p -R ¹⁴ '; p is 0, 1, 2, 3, 4 or 5; R ¹⁴ 'is cycloalkyl having 3, 4, 5 or 6 carbon atoms, tetrahydrofuranyl, tetrahydropyranyl, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ group, OCF ₃ group, NO ₂ group, CN group, COOMe group, CONH ₂ group, COMe group, NH ₂ group, OH group, 1-alkyl group , 2, 3 or 4 carbon atoms, an alkoxy group having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ² is H or alkyl having 1, 2, 3 or 4 carbon atoms; R ³ is an alkyl group having 3, 4 or 5 carbon atoms, a phenyl group wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, CF group _3, a group OCF _3z of NO _2, CN, COOMe, _CONH2, COMe, _NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or with 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group and a methylsulfonylamino group; R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , OCHF ₂ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; as well as their pharmaceutically acceptable salts. 104 Compounds of formula I according to claims 1 or 2, wherein R ¹ is a group 8 ^R \ R ^{10 R} \ X .O _x N A E 11 r-, 8 R ⁹ . R ^{12 R} x X RNA RNAE _ 10 ^{R 13} x X A x * or NA ^x E A is -C _n H _2n ^_; n is 0, 1, 2 or 3; O is an oxygen atom; D is a bond or an oxygen atom; E is -C _m H ₂ m ^- ; m is 0, 1, 2 or 3; R ⁸ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms; R ⁹ is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; R ¹⁰ is hydrogen, alkyl with 1, 2, 3 or 4 carbon carbon or cycloalkyl s 3, 4 or 5 flavors alkyl; R ¹¹ is a cycloalkyl group having 3,4, 5 or 6 carbon alkyl, phenyl or pyridyl group, wherein the phenyl group and the pyridyl group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a CF ₃ group, an OCF ₃ group, a NO ₂ group, a CN group, a COMe group OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ¹² is alkyl having 1, 2, 3 or 4 carbon atoms, cyklo105 alkyl having 3, 4, or 5 carbon atoms, aryl, or heteroaryl, where aryl and heteroaryl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, CF ₃ group, OCF ₃ group, NO ₂ group, CN group, COOMe group, CONH ₂ group, COMe group, OH group, 1, 2 alkyl group, 3 or 4 carbon atoms, alkoxy of 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ¹³ is C _p H ₂ p R ¹⁴ '; p is 0, 1, 2, 3, 4 or 5; R ¹⁴ 'is cycloalkyl having 3, 4, 5 or 6 carbon atoms, tetrahydrofuranyl, tetrahydropyranyl, aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a CF ₃ group, an OCF ₃ group, a NO ₂ group, a CN group, a COOMe group, a CONH ₂ group, a COMe group, an OH group, an alkyl group having 1, 2, 3 or 4 carbon atoms an alkoxy group having 1, 2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group and a methylsulfonylamino group; R ² is H or alkyl having 1 or 2 carbon atoms; R ³ is an alkyl group having 3, 4 or 5 carbon atoms, a phenyl group, wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, 106 of CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or with 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, bromine, CF ₃ , OCF ₃ , OCHF ₂ , NO ₂ , CN, COOMe, CONH _2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; as well as their pharmaceutically acceptable salts. Compounds of formula I according to claims 1 to 3, wherein R ¹ is a group R ⁹ X R ⁸ ^ X / R ¹¹ NAE A is -C _n H _2n ^-; n is 0, 1 or 2; O is an oxygen atom; E is -C _m H _{2 m} -; m is 0 or 1; R ⁸ is a hydrogen atom mama carbon; or alkyl group with 1, 2, 3 or 4 ató- R ⁹ is a hydrogen atom mama carbon; or alkyl group with 1, 2, 3 or 4 ató- R ¹⁰ is a hydrogen atom or alkyl group with 1 or 2 carbon 107 carbon; R ¹¹ is a phenyl group wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, an OC.F ₃ group, a CN group, a COMe group, an OH group, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ² is H; R ³ is an alkyl group having 3, 4 or 5 carbon atoms, a phenyl group wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, an OCF ₃ group, COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino ; R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, CF ₃ , OCF ₃ , CN, COOMe, CONH ₂ , COMe, OH, alkyl C 1, 2, 3 or 4 carbon atoms, C 1, 2, 3 or 4 alkoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; as well as their pharmaceutically acceptable salts. Compounds of formula I according to claims 1 to 3, wherein 108 R ¹ is a group A is -C _n H _2n -; n is 0, 1 or 2; D is a bond or an oxygen atom; E is -C _m H _2m -; m is 0 or 1; R ⁸ is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R ⁹ is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R ¹¹ is phenyl or pyridyl, wherein the phenyl or pyridyl is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , OCF ₃ , CN, COMe OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ¹² is alkyl having 1, 2, 3 or 4 carbon atoms or cyclopropyl; R ² is H; R ³ is an alkyl group having 3, 4 or 5 carbon atoms, a phenyl group wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, an OCF ₃ group, COOMe groups, CONH ₂ groups, COMe groups, 109 a OH group, an alkyl group having 1, 2, 3 or 4 carbon atoms, an alkoxy group having 1, 2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group and a methylsulfonylamino group; R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, CF ₃ , OCF ₃ , CN, COOMe, ΟΟΝΗ ₂ , COMe, OH, alkyl C 1, 2, 3 or 4 carbon atoms, C 1, 2, 3 or 4 alkoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; as well as their pharmaceutically acceptable salts. Compounds of formula (I) according to claims 1 to 3, wherein R ¹ is a group A is -C _n H _2n ^-; n is 0, 1 or 2; D is a bond or an oxygen atom; E is -C _m H 2 _m -; m is 0 or 1; R ⁹ is a hydrogen atom or an alkyl group having 1 or 2 carbon atoms; R ¹⁰ is H or alkyl having 1 or 2 carbon atoms; R ¹¹ is a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, a phenyl group wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group OCF ₃ , CN, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ¹³ is CpH _2p -R ¹⁴ '; p is 0, 1, 2, 3 or 4; R ¹⁴ 'is aryl or heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , OCF ₃ , CN, CN COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ² is H; R ³ is an alkyl group having 3, 4 or 5 carbon atoms, a phenyl group, wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, an OCF ₃ group , COOMe, _CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino j, sulfamoyl, methylsulfonyl and methylsulfonylamino; R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, fluorine, chlorine, CF ₃ , OCF ₃ , CN, 111 COOMe, CONH _2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; as well as their pharmaceutically acceptable salts. Compounds of formula I according to one or more of claims 1 to 6 and their physiologically acceptable salts for use as medicaments. Pharmaceutical composition, characterized in that it contains, as active ingredient, an effective amount of at least one compound of the formula I according to one or more of Claims 1 to 6 and / or its physiologically acceptable salts, together with pharmaceutically acceptable carriers and additives and, if appropriate, with one or more active substances. Use of a compound of formula I according to one or more of Claims 1 to 6 and / or a physiologically acceptable salt thereof for the preparation of a medicament with a K ⁺ -channel blocking action, for the therapy and prophylaxis of diseases mediated by a K ⁺ -channel. Use of a compound of formula I according to one or more of claims 1 to 6 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the therapy or prophylaxis of cardiac rhythm disorders which can be eliminated by prolonging the action potential. Use of a compound of formula I according to one or more of claims 1 to 6 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the therapy or prophylaxis of reentry arrhythmias. 112 Use of a compound of the formula I according to one or more of claims 1 to 6 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the therapy or prophylaxis of supraventricular arrhythmias. Use of a compound of formula I according to one or more of claims 1 to 6 and / or a physiologically acceptable salt thereof for the preparation of a medicament for the therapy or prophylaxis of atrial fibrillation or atrial flutter. Pharmaceutical composition, characterized in that it contains as active ingredients an effective amount of at least one compound of the formula I according to one or more of Claims 1 to 6 and / or a pharmaceutically acceptable salt thereof and a β-blocker, together with pharmaceutically acceptable carriers and additives. 15. A pharmaceutical composition, characterized in that as active ingredient an effective amount of at least one compound of formula I according to one or more of claims 1 to 6 and / or a pharmaceutically acceptable salt thereof and a blocker _of IK The conduit, together with a pharmaceutically acceptable carrier, and ingredients.